The chronic pain associated with cancer and other diseases affects every aspect of patients' lives, and is a significant factor in their quality of life throughout the course of the disease. Despite the ready availability of a number of treatments, the development of novel non-addictive analgesics represents a major thrust in biomedical research. This issue was recognized by the U.S. Congress, who recently named the years 2001-2010 "the decade of pain management and research." The search for new small molecules which effectively limit chronic pain continues on many fronts. One of the most successful methods to identify such molecules has been to study natural sources: for example, morphine, one of the oldest and most widely used pain medications, is a natural product. Other natural products with potential as analgesics have been identified as well, some of which are believed to lack the negative addictive qualities associated with morphine. The focus of this application is an example of such a lead compound: mitragynine pseudoindoxyl. Mitragynine pseudoindoxyl was isolated in 1970 as a minor metabolite of Mitragyna speciosa (commonly known as Kratom). This plant has been traditionally used to help drug users overcome addiction, and subsequent pharmacological investigation has revealed that mitragynine pseudoindoxyl is among the most potent compounds present in Kratom. Specifically, mitragynine pseudoindoxyl has been shown to be a specific opiate receptor agonist with a carbon skeleton distinct from morphine. Unfortunately, detailed SAR data and further in depth biological study of this compound have been hampered by lack of material and available analogs. This proposal aims to generate large quantities of mitragynine pseudoindoxyl and a variety of chemically diverse analogs by means of a novel chemical methodology. The realization of such compounds as novel non-addictive analgesics would have a significant impact on the quality of life of patients who suffer from chronic pain. The specific aims of this application are: (I) To complete an efficient total synthesis of the potent analgesic compound mitragynine pseudoindoxyl using an Ugi reaction and a metal mediated carbocyclization reaction as key steps, (II) To develop a novel multicomponent coupling reaction (the tandem Ugi/Houben-Hoesch reaction) to be utilized in the synthesis if possible, and (III) to design and synthesize a series of analogs of mitragyninie pseudoindoxyl using the tandem reaction developed in specific aim (II) to be assayed as potential novel analgesics. [unreadable] [unreadable] [unreadable]